METABOLIC, IMMUNE-MEDIATED, AND TOXIC NEUROPATHIES

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CHAPTER 83 METABOLIC, IMMUNE-MEDIATED, AND TOXIC NEUROPATHIES

Acquired peripheral neuropathy is a highly prevalent and often overlooked condition. Most patients and many physicians are not sufficiently aware of the range of disorders associated with neuropathy outside of the most common cause—diabetes mellitus. Although many neuropathies, including the roughly 30% that have no discernible cause, have no effective treatment, symptomatic therapy is available and therapeutic options are continually expanding. In contrast, many disorders discussed in this chapter can be potentially reversed or at least slowed by treating the underlying condition, removing offending toxins or medications, or limiting immune-mediated injury. For this to happen, proper diagnosis is essential. Several immune-mediated neuropathies are included here, but other important types of neuropathy are not discussed or are considered in more general sections on specific topics. Noteworthy examples include paraneoplastic neuropathy, hereditary and acquired amyloidosis, axonal paraprotein- and myeloma-associated, and acute immune-mediated neuropathies. Topics discussed in other sections include sarcoidosis, environmental toxins, nerve injury, and collagen vascular diseases.

NEUROPATHIES ASSOCIATED WITH DIABETES MELLITUS

Diabetes mellitus is the most common cause of neuropathy in the Western world, as noted since the early 1800s. The most common presentation is distal, predominantly sensory neuropathy; however, diabetes is associated with numerous other forms of neuropathy, ranging from asymptomatic to disabling motor, autonomic, or pain syndromes (Table 83-1). This syndromic list is both clinically and experimentally useful because the differing underlying mechanisms that are likely to occur directly influence treatment choices and efficacy, clinical trial selection, and mechanistic bench research. Most published lists differ slightly in syndrome numbers and entity names, and a separate list could be based on probable pathophysiological mechanisms.¹ Important clinical features include nerve modalities, symmetry, speed of onset, distribution, and related diabetic complications, especially renal failure. A consensus statement in 2005 reviewed clinical syndromes, pathogenic mechanisms, and recommended treatment.² There is growing evidence that symptomatic peripheral neuropathy can occur in the presence of mild diabetes or glucose intolerance even in the absence of notable damage to other end organs. However, in most large series, neuropathy is associated with both retinopathy and nephropathy.³ Less common forms of diabetic neuropathy are not associated with diabetic complications, suggesting a different pathophysiology, such as inflammatory or immune-mediated injury. Conversely, the coexistence of diabetes and neuropathy in a particular patient is not in itself proof of diabetic neuropathy, as unrelated processes may be present that warrant appropriate diagnostic investigation. In general, any of the entities listed can occur with either type 1 or type 2 diabetes (Table 83-1).

TABLE 83-1 Clinical Neuropathy Patterns Associated With Diabetes Mellitus

Distal Diabetic Polyneuropathy

Foot numbness and paresthesia have gradual onset and ascend slowly. The process can spread to the hands, arms, trunk, and scalp in advanced cases, but more commonly hand and arm involvement is caused by superimposed processes, such as compressive mononeuropathy.³ Loss of light touch, pain, and temperature precede loss of proprioception; distal weakness and atrophy are late findings. Patients generally notice “positive” or unpleasant symptoms, especially burning pain, electrical or stabbing sensations, paresthesia, and deep pain; loss of sensation and anesthesia are less common. Symptoms are frequently worse at night when there are less sensory distractions. Approximately 20% to 50% of diabetic patients have at least one symptom of diabetic neuropathy but even more have asymptomatic disease. Lack of sensation can lead to unperceived injury, ulcers, and Charçot joints—a significant form of morbidity. Not surprisingly, objective evidence of functional loss on clinical examination and laboratory testing often exceeds symptoms. Onset may occur after several years of diabetes or with subclinical diabetes, and the neuropathy may lead to the discovery of underlying diabetes. Sensory fibers in the foot and distal leg are predominantly affected, especially small diameter sensory and autonomic fibers. Examination of the lower leg usually reveals loss of vibration, pressure, pain, and temperature perception (both small and large fiber-mediated) and absent ankle deep tendon reflexes. Signs of peripheral autonomic (sympathetic) dysfunction are frequent, including altered skin temperature (cold or warm), dry, often scaly, skin, and calluses in pressure-bearing areas. Loss of sensation for 128-Hz vibration, monofilament touch, and loss of ankle jerks are considered 87% sensitive for detecting neuropathy and predicting foot ulcer.² The diagnosis is ultimately clinical and requires exclusion of other reasonable causes of neuropathy. Even if symptoms remain confined to the legs and feet, objective testing such as nerve or skin biopsy and clinical electrophysiological studies often show evidence of more widespread involvement. Electrodiagnostic studies are an important adjunct to assess severity and to parse out superimposed mononeuropathy, regional syndromes, superimposed radiculopathy, and demyelinating neuropathy. Nerve biopsy is not routinely necessary but in some cases it demonstrates signs of microvascular changes in addition to axonal loss (Fig. 83-1). Skin punch biopsy to assess epidermal nerve fiber density is increasingly available and minimally invasive, as discussed later.

Figure 83-1 Diabetic neuropathy, sural nerve. The tissue section of the nerve shows a mild loss of myelinated fibers. Endoneurial microvessels show a collar of hyaline pink material, a characteristic feature of diabetic microangiopathy (semithin plastic sections, toluidine blue-basic fuchsin).

(Courtesy of Arthur P. Hays, MD, Associate Professor of Clinical Pathology, Columbia University, New York, NY.)

Diabetic autonomic neuropathy affects up to one half of diabetics.³ Genitourinary and sexual dysfunction, such as impotence, are most common, but orthostatic intolerance and hypotension, gastrointestinal dysmotility (diarrhea or constipation), gastroparesis, fatigue and exercise intolerance, vasomotor disturbance, and pupil dysfunction are also common. Patients with diabetic autonomic neuropathy have shorter survival than do unaffected diabetic patients, but the relative risk is less than early reports suggested. Patients may become intolerant of autonomically active medications, such as antihypertensive or anticholinergic agents, as the neuropathy slowly worsens, producing symptoms such as orthostatic complaints, syncope, urinary retention, excessively dry eyes, and focusing difficulties. Formal autonomic testing is widely available and is especially helpful when the clinical picture is equivocal or the cause of orthostatic symptoms is unclear. Treatment and assessment are discussed in Chapters 29 through 32 Chapter 30 Chapter 31 Chapter 32. The pathophysiology is presumed to be the same as in distal diabetic polyneuropathy and is discussed later.

Ischemic mononeuropathies are presumably due to occlusion of arterioles supplying individual nerves and produce acute ischemia and aching pain, followed by loss of nerve function. The process can affect either cranial or peripheral nerves or nerve roots. Pupil-sparing oculomotor palsy is the most common cranial neuropathy, followed by sixth and seventh neuropathies, but all are relatively uncommon. Diabetics are more susceptible to compression or entrapment neuropathy, and at least 30% of diabetics have carpal tunnel syndrome, which can range from asymptomatic to very distressing.¹ Ulnar neuropathy at the elbow, peroneal neuropathy at the fibular head, and lateral femoral cutaneous neuropathy (meralgia paresthetica) are also common.

Diabetic amyotrophy (diabetic radiculoplexus neuropathy) is a monophasic illness seen primarily in type 2 diabetic patients and characterized by subacute proximal leg weakness progressing stepwise over weeks to months, weight loss, atrophy, and aching proximal leg pain. The weakness affects mostly but not exclusively the femoral and obturator nerve distributions, plateaus over weeks, and slowly improves over 12 to 36 months.⁴ Sensory involvement is less marked and often overshadowed by the underlying distal polyneuropathy. Anatomic boundaries are not respected, and there is often evidence of both nerve root and plexus involvement, hence the descriptive label. Findings may be unilateral or bilateral but asymmetric. If involvement is extensive, a diagnosis of chronic inflammatory demyelinating polyneuropathy, which is more common in diabetic patients, should be considered. Thoracic and cervical forms also occur but are less common and must be distinguished from ischemic injury and unrelated compressive spine disease. Although various neuropathological findings have been reported, an immune-mediated process is suspected and a long-awaited treatment trial is ongoing.

Etiology

There are numerous lines of evidence and hypotheses attempting to explain diabetic polyneuropathy but most start with perturbations initiated by excessive glucose levels. Duration of diabetes, hemoglobin A1c levels, and other signs of poor glucose control correlate with neuropathy development and severity. Microvascular injury appears to be a crucial process in the development of neuropathy as well as in damage of other end organs, and interruption of this process has long been a target of therapeutic intervention. Four major pathways of glucose metabolism are implicated. Excess intracellular glucose is processed, in part, through the polyol pathway in a series of reactions catalyzed by aldose reductase. This pathway leads to sorbitol and fructose accumulation, NAD(P)H-redox imbalances, changes in signal transduction, and excessive production of reactive oxygen radicals.⁵ Also, nonenzymatic glycation of proteins produces advanced glycation end products in peripheral nerve, and these impair axonal transport, neurotrophic factor production, and gene expression. In addition, protein kinase C activation starts a cascade of stress responses and increases hexosamine pathway flux; both processes lead to oxygen radical generation.⁵ Specific inhibitors of each pathway, aimed at blocking one or more microvascular complications, have shown considerable promise in rodent models: they include nine different aldose reductase inhibitors, various neurotrophins, blood flow and angiogenesis enhancers, free radical scavengers, and others. Unfortunately, virtually all have failed or have produced equivocal results, but several trials are presently ongoing, including a gene therapy trial of vascular endothelial growth factor. A broader approach targeting several pathways at once may be needed to affect human disease. Other risk factors have gathered recent attention. A large European consortium has found the following independent risks factors for the cumulative incidence of diabetic neuropathy: low-density lipoprotein cholesterol and triglycerides, high body mass index, high von Willebrand factor levels and urinary albumin excretion rate, hypertension, and smoking.⁶ Several factors are potentially adjustable and some might explain why neuropathy develops in patients with early disease or with simple glucose intolerance, as we discuss later. More acute or subacute entities suggest an immune-mediated mechanism, and some may respond to immunomodulating therapies.

Treatment

Tight glycemic control is the most important and only intervention proved to prevent or limit diabetic polyneuropathy and autonomic neuropathy, but it does not reverse existing nerve injury.^7,⁸ Treatment of other modifiable potential risk factors (lipids, blood pressure, weight) is an evolving but likely important approach. The efficacy of preventative medications currently in clinical trials is yet to be determined.

Numerous symptomatic treatments are effective in reducing—but usually not eliminating—the discomfort of diabetic and other painful polyneuropathies. Randomized double-blind, controlled trials have demonstrated symptomatic relief, primarily for painful neuropathy, with a number of agents, including several tricyclic antidepressants, gabapentin, pregabalin, tramadol hydrochloride, and the serotonin and norepinephrine reuptake inhibitor duloxetine.^1,⁹^–¹¹ The selective serotonin reuptake inhibitor paroxetine was better than placebo but not better than imipramine, and citalopram was similar to paroxetine; fluoxetine showed no significant benefit. However, only pregabalin and duloxetine have received U.S. Food and Drug Administration indications for treatment of painful neuropathy. Numerous other medications and therapies have undergone small randomized or incompletely controlled trials and are empirically used. Proper foot care and prompt attention to injury are essential.

Glucose Intolerance and Neuropathy

There is increasing recognition of impaired glucose tolerance, sometimes designated as prediabetes, in patients with painful sensory neuropathy, as many as 34% in one study.¹²^–¹⁴ Fasting plasma glucose of 100 to 125 mg/dL or 2-hour glucose of 140 to 199 mg/dL (impaired glucose tolerance) defines prediabetes. The 2-hour oral glucose tolerance test is the usual detection method and is recommended in patients with otherwise unexplained sensory neuropathy. Autonomic dysfunction appears to be common in these patients.¹⁵ The mechanism of nerve damage in hyperglycemia is still unknown, but early indications suggest that aggressive lifestyle modifications affect neuropathy progression and are the target of a multicenter clinical trial. Most patients with neuropathy associated with prediabetes are overweight and show metabolic manifestations of insulin resistance. Treatment of hyperglycemia, insulin resistance, neuropathic pain, and individualized diet and exercise counseling have been more effective than glucose-lowering medications in preventing progression from impaired glucose tolerance to diabetes.¹⁴ Diet and exercise also seem to reduce neuropathic pain in these patients.

Other Endocrine Disorders

Hypothyroidism is uncommonly associated with peripheral neuropathy and frequently with carpal tunnel syndrome. Acromegaly is associated with entrapment neuropathy.

Small Fiber Neuropathy

Small fiber neuropathy is an increasingly diagnosed disorder with pure or predominant involvement of small-diameter myelinated and unmyelinated sensory and autonomic nerve fibers and with minimal or no large fiber sensory or motor impairment. Common manifestations include pain, burning distal paresthesia, impaired temperature perception, trophic signs, distal autonomic dysfunction, especially impaired vasomotor and temperature control, and decreased sweating. Diabetes is the most common cause, and findings are indistinguishable from early distal diabetic polyneuropathy. Other important or common causes include amyloidosis, chronic alcoholism, certain toxins, and rare hereditary entities. However, in a substantial group of patients there is no discernible cause.

Because most conventional tests, such as nerve conduction studies, do not assess small-diameter fibers, other objective means to confirm this syndrome are desirable. Quantitative sensory testing assesses small and large sensory fibers by examining temperature and vibratory thresholds; although useful for sequential measures in clinical trials, it is not recommended for routine clinical diagnostic use.^16,¹⁷ Epidermal nerve fiber density measured from skin punch biopsies is rapidly increasing in popularity and availability as a simple and minimally invasive technique. The small skin sample is stained immunohistochemically with antibodies against nerve-specific protein gene product 9.5 (PGP9.5).¹⁸^–²⁰ Most frequently, there is a reduction in nerve fiber numbers, worse distally, but axonal swellings also correlate with disease²¹ (Fig. 83-2). Sensitivity ranges from 74% to 87%. Distal autonomic function measures correlate better with epidermal nerve fiber density than cold perception thresholds and are significantly better than sural sensory nerve amplitude in documenting the selective loss of small diameter fiber function.^17,¹⁹ Quantitative sudomotor axon reflex testing, which evaluates postganglionic sympathetic sudomotor function by measuring evoked sweat after acetylcholine iontophoresis, is the best validated technique in this condition, but other methods are also employed; current clinical and common research methods are listed in Table 83-2. Treatment is similar to that of diabetic and other painful forms of neuropathy covered previously.^20,²²

Figure 83-2 Epidermal nerve fibers of the calf in a normal individual and a patient with small fiber neuropathy. A, Skin biopsy of a healthy person shows two axons that extend perpendicularly to the skin surface toward the layer of keratin. The epidermal nerve fiber density was 10.5 fibers/mm. B, Skin biopsy from a patient with a small fiber neuropathy demonstrating severe loss of epidermal nerve fibers. Some of the few remaining nerve fibers have focal swelling of the axons as exemplified in this image. The epidermal nerve fiber density was 2.0 fibers/mm. Both skin specimens were fixed by periodic acid-lysine-paraformaldehyde and stained by immunoperoxidase method for the panaxonal marker PGP9.5.

(Courtesy of Arthur P. Hays, MD, Associate Professor of Clinical Pathology, Columbia University, New York, NY.)

TABLE 83-2 Clinical and Research Tools for Small Fiber Neuropathy Testing

Epidermal nerve fiber density (skin punch biopsy)

Quantitative sudomotor axon reflex testing

Cardiovascular autonomic reflex testing

Quantitative sensory testing

Laser Doppler reflex testing (limited availability)

Sural nerve biopsy electron microscopy small fiber counts (tedious and rarely performed)

Uremic Neuropathy

Neuropathy is associated with chronic renal failure; some patients also have coincident diabetes. This is a distal symmetrical sensorimotor polyneuropathy possibly caused by uncharacterized uremic toxins. It is present in as many as 60% to 70% of patients with chronic renal failure, but patients are often asymptomatic and the neuropathy is identified only by nerve conduction studies.²³ Symptoms are insidious and include painful dysesthesia, stocking-glove loss of sensation, and mild distal muscle weakness. Autonomic dysfunction is generally not as severe as with diabetes. Neuropathy typically occurs when the glomerular filtration rate falls below 20 mL/min and undialyzable toxins accumulate.²⁴ Sensory and motor conduction velocities are mildly reduced, and evoked motor and sensory nerve response amplitudes are reduced. Pathologically, there is axonal degeneration of the most distal nerve trunks with secondary segmental demyelination.

Without dialysis or renal transplantation, prognosis is poor and the neuropathy progresses. With peritoneal or hemodialysis, the neuropathy stabilizes. Improvement after transplantation, sometimes with complete resolution of symptoms in as few as 1 to 3 months, is reported.^25,²⁶

Neuropathy Associated With Hepatic Disease

Peripheral neuropathy is rarely associated with primary liver diseases. A painful sensory neuropathy is associated with primary biliary cirrhosis and is probably caused by xanthomas forming in and around nerves. Infectious diseases of the liver and hereditary disorders with liver involvement (porphyria) are also associated with peripheral neuropathy but are discussed elsewhere. Immune-mediated diseases, such as polyarteritis nodosa and sarcoidosis, may cause both liver dysfunction and neuropathy, notably mononeuropathy multiplex.

SELECTED CHRONIC IMMUNE-MEDIATED NEUROPATHIES

Acquired Chronic Immune-Mediated Neuropathies

There is some disagreement on which entities in this category should be grouped under the unifying term chronic inflammatory demyelinating neuropathy and which variants should be separated into discrete entities. The definitive diagnosis of the classic form of chronic inflammatory demyelinating neuropathy is also debated and a number of diagnostic criteria have been proposed.²⁷^–³² The cardinal features of classic chronic inflammatory demyelinating neuropathy include progressive symptoms for more than 2 months (to differentiate from Guillain-Barré syndrome), predominant motor findings, symmetrical distal and proximal arm and leg involvement, reduced or absent deep tendon reflexes, increased cerebrospinal fluid protein, primary signs of demyelination on electrodiagnostic studies, and segmental demyelination on nerve biopsy. Not all treatment-responsive patients have all clinical or laboratory characteristics. Elevated cerebrospinal fluid protein and nerve biopsy are not required by all classifications. Magnetic resonance imaging may demonstrate gadolinium enhancement or increased T₂-signal abnormalities in proximal nerves or nerve roots.

The stringent 1991 American Academy of Neurology subcommittee criteria were intended for uniformity in clinical trial enrollment, not for routine clinical application, but were used for lack of widely accepted scales ³¹; more recent criteria deemphasize some features, sacrificing specificity to improve sensitivity.^30,³² The cited prevalence is 0.5 of 100,000 children and 1 to 2 of 100,000 adults.²⁹ The course may be relapsing or progressive but relapsing forms are more common in younger patients.³³ Secondary axonal loss occurs, likely as a concomitant injury, but is critical for treatment response, long-term disability, and prognosis. Early effective treatment is the best means to limit this process.

Pathogenesis

An autoimmune process with activation of autoreactive T and B cells is presumed but specific targets have not been identified. The migration of activated T cells across the blood-nerve barrier is being actively investigated. Autoantibodies are also presumed to exist, and sera from chronic inflammatory demyelinating neuropathy patients do induce conduction block in animals, but specific antibodies have not been identified other than in some well-defined syndromes.

Treatment

Randomized controlled trials have demonstrated the effectiveness of corticosteroids, plasmapheresis, and intravenous immunoglobulin and found no significant difference between these treatments, but intravenous immunoglobulin and steroids are recommended as first line treatment.³⁴ Most studies, however, have been short in duration. Interferon β-1a was effective in open label but not in controlled trials of treatment-resistant patients. Adhering to published criteria does not seem to predict treatment responsiveness.³⁵ Use of other medications is supported by open trials or empiric use: these include azathioprine, cyclophosphamide, mycophenolate mofetil, etanercept, and cyclosporin A. To further complicate matters, a rare treatment-responsive chronic inflammatory demyelinating neuropathy-like illness appears to be triggered by the immunomodulatory agents interferon-α or -β, tumor necrosis factor α antagonists, tacrolimus, and cyclosporin A.

Associated Conditions

A number of conditions are associated with otherwise typical CIDP, including HIV infection, hepatitis virus B and C infection, collagen vascular disease (especially systemic lupus erythematosus and Sjögren syndrome), lymphoma, melanoma, inflammatory bowel disease, and Charçot-Marie-Tooth disease. Increased incidence of demyelinating neuropathy has been noted in patients with diabetes, who appear to respond well to immunomodulatory treatment.³⁶ The appearance of a subacute predominantly motor, symmetrical proximal and distal subacutely worsening neuropathy should raise this concern.

Chronic Inflammatory Demyelinating Neuropathy Variants

Paraprotein-Associated Demyelinating Neuropathy

Demyelinating polyneuropathy is also associated with paraproteins, most commonly IgM and less clearly IgA or IgG. Overall, polyneuropathy occurs in 5% of patients with paraproteins, but most have only mild distal axonal sensorimotor neuropathy; some have associated amyloidosis. One third of patients with isolated monoclonal gammopathy of uncertain significance eventually develop myeloma or other hematological malignancy. Osteosclerotic myeloma is a rare form of myeloma (3%) in which one half of patients develop neuropathy, usually demyelinating and usually discovered prior to the myeloma. This entity overlaps with POEMS syndrome and associated variants that are characterized—in addition to neuropathy—by organomegaly, endocrinopathy, and skin changes, although only about 15% have the complete syndrome. Sensory neuropathy is most commonly associated with antibodies to sulfatide, but 30% of patients with antibody titers have demyelinating neuropathy with or without a paraprotein.³⁸

Some patients have symmetrical but predominantly distal rather than proximal involvement, a condition descriptively labeled distal acquired demyelinating symmetrical neuropathy. Older men are most frequently affected and roughly two thirds of them have IgM paraproteins, some of which are directed against myelin-associated glycoprotein. Anti-myelin-associated glycoprotein antibodies bind to distal nerve segments and produce a distinctive electrophysiological picture with demyelinating signs preferentially affecting the most distal nerve segments and resulting in markedly increased distal motor latencies. These patients generally respond poorly to conventional immunosuppressive therapy. Recent treatment attempts with the anti-B cell monoclonal antibody agent rituximab are promising.

Multifocal Motor Neuropathy

Multifocal motor neuropathy is an acquired immune-mediated neuropathy characterized by slowly progressive asymmetrical arm and leg weakness sparing cranial nerves, and beginning in a single peripheral nerve distribution. Typically, there is painless weakness, focal wasting, and sporadic fasciculations with preserved or absent tendon reflexes, although minor sensory complaints may also be present.³⁹ These features can be confused with lower motor neuron disease in the early stages. However, unlike motor neuropathy, clinical weakness is generally out of proportion to atrophy, manifestations are characteristically asymmetrical and progression is slow. Men are more frequently affected with an average age of onset around 40 years.

Electrophysiological evidence of denervation is accompanied by the defining abnormality—multifocal motor conduction block, that is, the failure of a nerve impulse to conduct through an intact axon away from typical sites of nerve compression. However, lesser signs of demyelination, such as temporal dispersion, and minor sensory abnormalities are also described.⁴⁰ Multifocal conduction block is the diagnostic hallmark but treatment-responsive patients with other electrophysiological abnormalities have prompted a search for additional diagnostic techniques. Ultrasonographic nerve enlargement has been noted.⁴¹ More sophisticated nerve stimulation techniques, such as magnetic stimulation and multiple stimuli, have documented proximal conduction block undetectable with conventional techniques.⁴² The underlying pathology is presumed to be immune mediated but predominantly restricted to motor fibers, making biopsy of a sensory nerve uninformative; a few such biopsy samples have shown little or no pathological changes. Motor nerve biopsies have shown variable features, including demyelination, rare focal inflammatory changes, frequent axonal loss, and signs of axonal regeneration.⁴³ Some of these features are illustrated in Figure 83-3.

Figure 83-3 Multifocal motor neuropathy, motor nerve to the gracilis muscle. This transverse section of a motor nerve shows a mild loss of myelinated fibers, prominent regenerative clusters of small myelinated fibers (arrowheads) and small onion bulbs (arrows). A second nerve fascicle (not shown) did not exhibit regenerative clusters or onion bulbs (semithin plastic sections, toluidine blue-basic fuchsin).

(Courtesy of Arthur P. Hays, MD, Associate Professor of Clinical Pathology, Columbia University, New York, NY.)

Increased titers of IgM anti-GM₁ gangliosides are found in 30% to 50% or even more patients in different series; anti-GD_1a antibodies are found less frequently.^39,⁴⁴ The pathogenicity of these antibodies remains uncertain, especially because most patients have no measurable titers. Other proposed mechanisms include antibody-mediated blockade of Na⁺ and K⁺ channels at the nodes of Ranvier. Sophisticated electrophysiological techniques suggest that focal depolarization or hyperpolarization may explain how conduction may be impaired without easily identifiable conduction block and how some patients may respond promptly to treatment.⁴⁵ Cerebrospinal fluid protein is generally normal.

The prime importance of a correct diagnosis is that the weakness of multifocal motor neuropathy is potentially reversible with intravenous immunoglobulin treatment; there is partial to complete improvement of symptoms and decrease of anti-GM1 antibody titers. Improvement begins within 14 days and lasts an average of 2 months, although intravenous immunoglobulin effectiveness may decrease after years of treatment. Conduction block is not a permanent state and eventual axonal loss may ensue, especially if the condition is not treated. Unlike in chronic inflammatory demyelinating neuropathy, steroids are ineffective. Other immunosuppressive agents have been empirically used on the basis of open label trials, but no controlled trials have been conducted for cyclophosphamide, plasmapheresis, mycophenolate mofetil, azathioprine, rituximab, and some other agents.

Multifocal Sensorimotor Demyelinating Neuropathy

Multifocal motor neuropathy is distinctively motor but may include minor sensory symptoms and findings. A separate syndrome, described in 1982 by Lewis and Sumner, is characterized by multifocal motor and sensory involvement, unlike either chronic inflammatory demyelinating neuropathy or multifocal motor neuropathy (Lewis-Sumner syndrome).⁴⁶ Some prefer the cumbersome descriptive term multifocal axonal acquired demyelinating sensory and motor neuropathy. Also in contrast to multifocal motor neuropathy, male predominance is not seen, steroid-responsiveness is common, GM₁ antibodies are absent, and sensory nerves demonstrate segmental demyelination and inflammatory cells. The clinical picture is closer to vasculitic neuropathy, from which it must be differentiated, but some cases are difficult to distinguish from multifocal motor neuropathy or chronic inflammatory demyelinating neuropathy. Many but not all respond to prednisone or intravenous immunoglobulin, but most respond to some form of immunotherapy.⁴⁷

Vasculitic neuropathy characteristically manifests as mononeuropathy (mononeuritis) multiplex or distal symmetrical polyneuropathy. The disorder is associated with primary vasculitis, connective tissue disorders, and certain infections and malignancies. The process is most commonly systemic but isolated neuropathy can also occur. Onset is usually acute or subacute with painful severe weakness and sensory loss in the distribution of individual peripheral and cranial nerves. Progress is most commonly stepwise, but 25% to 30% of patients have distal and symmetrical neuropathy with steady progressive worsening.^48,⁴⁹ Rarely, patients have a chronic and indolent course.⁴⁹

The etiology of vasculitic neuropathies is unknown, but the process is presumed to be immune mediated. One half of the cases occur in the setting of collagen vascular disease, and 10% are associated with malignancy, drug ingestion, or infection. Neuropathology reveals necrotizing arteritis with transmural inflammatory infiltration and fibrinoid vessel wall necrosis, lumen reduction, and signs of focal nerve ischemia, mostly in myelinated fibers. The ischemia leads to focal axonal degeneration of individual nerve fascicles.⁵⁰ The diagnosis is established by the characteristic findings in biopsy samples of nerve, muscle, or both. The biopsy specimen, however, may show only axonal degeneration if the sample is distal to the infarct or if the specimen includes no affected vessels. Multiple levels may need to be sampled to increase the diagnostic yield. Nerve conduction studies may show electrical inexcitability of nerve segments distal to a site of infarct. If some nerve fascicles are selectively spared, conduction velocity is preserved but the evoked amplitude is diminished.

Polyarteritis nodosa affects medium-size vessels and is the most common and most important cause of vasculitic neuropathy. Clinical neuropathy occurs in 50% to 75% of polyarteritis nodosa patients. Skin involvement is frequent and diagnostically useful. The clinically similar Churg-Strauss syndrome, associated with asthma and eosinophilia, is probably a polyarteritis nodosa variant. Vasculitis in association with rheumatoid arthritis is also common and often associated with poor outcome. Other important associations include Sjögren syndrome, systemic lupus erythematosus, systemic sclerosis, and Wegener’s granulomatosis. Important conditions associated with vasculitic neuropathy are cryoglobulinemia, viral infections, and malignancy, especially T cell lymphoma. Sarcoidosis also can produce mononeuropathy multiplex.

Immunosuppression is the primary treatment. For systemic vasculitis, prednisone (1 to 1.5 mg/kg) and cyclophosphamide (2 mg/kg) are most commonly used. In nonsystemic vasculitic neuropathy, prednisone is usually given alone. Plasmapheresis is used for cryoglobulinemia; empirical open-label benefit of intravenous immunoglobulin in treatment-resistant patients is reported.⁵¹

Prognosis has been described only in anecdotal studies. Eighty percent of nonsystemic vasculitis patients improve, but the 5-year survival rate is 37% to 48% for treated systemic vasculitis patients and only 15% for untreated patients.^48,⁵⁰

IATROGENIC AND TOXIC NEUROPATHY

Iatrogenic and Toxic Neuropathies

Although patients frequently suspect medications or toxins to cause otherwise unexplained peripheral neuropathies, drugs and toxins are, in fact, the cause of an estimated 2% to 4% of peripheral neuropathies.^52,⁵³ Toxic neuropathies, including medication-induced forms, generally induce axonal degeneration in a “dying back” axonal pattern. Any disturbance of axonoplasmic flow disproportionately affects the distal segments of the most vulnerable nerves, producing a uniform distal stocking-glove pattern of involvement. However, some agents cause segmental demyelination; injure Schwann cells, dorsal root, or autonomic neurons; or damage peripheral myelin. Onset is generally over weeks to months, and causation is best established by a strong dose-response relationship, consistent manifestations, close proximity of symptoms to exposure, stabilization or improvement after drug cessation, reproduction in animal models, and exclusion of other causes.⁵⁴ However, some agents have idiosyncratic, delayed, or cumulative effects, their mechanisms of clearance are different in animals, and recovery is poor or delayed recovery because of axonal degeneration or neuron loss, making a definitive association problematic. In addition, some patients continue to worsen even after agent cessation, usually for several weeks, a phenomenon termed “coasting,” which clouds definitive diagnosis. A variety of neurotoxic mechanisms are known, including direct toxicity or toxicity mediated by metabolites, secondary vitamin deficiency, interference with DNA or metabolic function, mitochondrial injury, apoptosis, and immune triggers. Other factors, such as preexisting neuropathy, decreased toxin metabolism or clearance, or genetic profile may predispose to neurotoxicity. Despite these limitations, it is critical to look for the associations described above, so that an offending agent can be promptly stopped, which sometimes leads to improvement. Some agents have only a weak temporal association with neuropathy in rare patients, whereas others are clearly linked to neuropathy, which limits their use.

Medications continually increase in number, and uncommon side effects may not become apparent until their use is widespread. A number of agents produce tolerable neuropathies given the severity of the underlying disease, notably malignancies and HIV infection. In these cases, evolving research has been directed toward identifying secondary agents or delivery methods that would blunt or prevent toxicity. Identification of a toxic effect is easy when symptoms develop acutely or subacutely soon after initial drug exposure or after a change in medication dosage. Most cases fall into this category. More problematic is diagnosing a slowly progressive neuropathy starting months or years after initiation of therapy. Statins provide a case in point and are discussed below.

The blood-nerve barrier is partially protective but is less efficient than its blood-brain barrier counterpart. This and other factors make peripheral nerves more susceptible than central nerves to certain toxins. Decreased drug metabolism or clearance due to impaired hepatic or renal function can lead to the buildup of toxic agent levels, notably in the elderly. The presence of a preexisting neuropathy, whether hereditary or acquired, can predispose to neurotoxicity. Some common and more clinically relevant associations are briefly discussed; others are listed in Table 83-3.

TABLE 83-3 Medications With Probable to Well-Established Toxic Neuropathy Association

Antibiotics and Antivirals

Dapsone

Ethambutol (optic)

Linezolid (Zyvox)

Metronidazole (Flagyl)

Nitrofurantoin

Nucleoside reverse transcriptase inhibitors (some agents)

Podophyllin resin

Chemotherapeutic Agents

Taxoids (Paclitaxel, Docetaxel)

Vincristine

Thalidomide

Cardiovascular Agents

Other Agents

Proton pump inhibitors (lansoprazole, omeprazole)

Pyridoxine

Tacrolimus (FK-506, Prograf)

Antibiotics

Nucleoside analogs—some, but not all, nucleoside reverse transcriptase inhibitors are associated with a dose-dependent peripheral neuropathy. Examples include zalcitabine (ddC), didanosine (ddI), stavudine (ddT), and lamivudine (3TC). This distal painful sensory axonal neuropathy usually begins 6 to 8 weeks after initiating treatment. Signs and symptoms include burning dysesthesia in the legs, impaired sensation, minimal weakness, and absent ankle jerks. The process may be indistinguishable from AIDS-related neuropathy, including electrophysiological testing. The neuropathy improves after drug discontinuation, often within a month. The mechanism of neuropathy may be related to the inhibition of DNA polymerase gamma and mitochondrial DNA replication. Risk factors for nucleoside reverse transcriptase inhibitor neuropathy include a CD4 count of less than 100 cells/mm³, combination drug therapy, and underlying neuropathy.⁵²

Isoniazid can occasionally cause a dose-related sensory axonal polyneuropathy, typically after 4 to 6 months of use. Toxicity usually occurs at doses over 300 mg/day and can be prevented with pyridoxine supplementation. Isoniazid toxicity is mediated by inhibition of pyridoxine-dependent enzymes and occurs in vulnerable populations, such as alcoholics and malnourished patients.

Dapsone can cause a motor-predominant neuropathy, an unusual toxic effect, but one that helps distinguish drug toxicity from lepromatous neuropathy in patients undergoing Dapsone treatment. The distribution is atypical, affecting the arms more than the legs. The neuropathy is dose related and occurs after prolonged exposure.

Linezolid, approved in 2000, is an oxazolidinone, the first new class of antibiotics approved in 40 years. It has activity against drug-resistant enterococci, Staphylococcus aureus, and Bacillus tuberculosis, making prolonged use desirable. Optic and sensory neuropathies are both well documented and growing concerns with extended use.^55,⁵⁶

Metronidazole is used to treat both protozoan and anaerobic bacterial infections. A predominantly sensory axonal neuropathy is a potential and underappreciated neurotoxic effect.⁵⁷ Chronic treatment and high doses are risk factors, although symptomatic polyneuropathy was reported after a total of 1200 mg/day for only 9 days.⁵⁸ Sural nerve biopsies show degeneration of both myelinated and unmyelinated sensory fibers. The radiosensitizing agent misonidazole is chemically related and also associated with neuropathy.

Nitrofurantoin is still used to treat urinary tract infections. Exposure can cause sensorimotor axonal neuropathy. Patients with impaired renal function are at greater risk.

Cardiovascular Agents

Statins are notoriously associated with myopathy, but the evidence for toxic polyneuropathy was based on a series of case reports until a well-publicized large case-control series from Denmark suggested a 4- to 14-fold increased risk of developing “idiopathic” neuropathy in patients on statins.⁵⁹ However, the methodology used in this study has generated some criticism.⁶⁰ Identifiable causes of neuropathy were carefully excluded but the study was unable to control for undiagnosed or latent diabetes; also, recent evidence suggests that hyperlipidemia may be an independent neuropathy risk factor.⁶ The ascribed neuropathy is a nonspecific axonal sensorimotor neuropathy. Because these agents are so widely used, concern for causation is frequent in patients with new-onset neuropathy; a period off medication is probably the best current method to test the association in a patient. However, this entity is probably very rare.

In amiodarone users, polyneuropathy is the second most common neurological side effect, after tremor, occurring in 6% of those taking it for several months,^61,⁶² usually in dosages greater than 400 mg/day. Sensorimotor neuropathy is most common and can be severe; motor and autonomic involvement is also seen and can also be severe. Nerve conduction studies and neuropathology show evidence of axonal loss, demyelinating features, or a combination of the two. Symptoms usually improve after drug cessation or lowering the dosage. The mechanism of toxicity is unknown but amiodarone enters lysosomes and irreversibly binds polar lipids; characteristic intralysosomal inclusions are seen in many tissues, including Schwann cells and peripheral neurons.⁶³ Drug metabolite levels are 80-fold higher in nerve than in serum.⁶¹ Demyelinating neuropathy and lipid inclusions are also found in patients treated with another lipophilic cardiac drug, perhexiline, which has never been approved in the United States but is still used in Europe.

Chemotherapeutic Agents

Some degree of neuropathy is to be expected with certain agents, but the effects of neuropathic symptoms on the quality of life should be considered. Most agents are neurotoxic in a dose-dependent manner, either with a single high dose or with cumulative lower doses ⁶⁴; a lower dose may produce less toxicity but may reduce efficacy. Pretreatment with neuroprotective agents is of prime interest but not adequately investigated. Many agents have shown promise in animal models but few have performed as impressively in clinical trials. To date, amifostine is the only approved medication to blunt chemotherapeutic toxicity, primarily by reducing cisplatin toxicity on the kidney but not on peripheral nerves. Other agents have shown partial benefit in human trials, but the only drugs that appear to markedly blunt or prevent neuropathy in experimental models are neurotrophins; however, none is currently undergoing study.

Vincristine, a vinca alkaloid, causes axonal neuropathy in virtually all users, depending on dose, and neuropathy is often a dose-limiting effect. The neuropathy begins with distal pain, paresthesia, and absent ankle jerks, followed by weakness, which can be severe, and generalized areflexia; autonomic and cranial neuropathies are also seen. Electrophysiological studies show reduced sensory and motor responses. Because of the axonal loss, improvement may be delayed or incomplete in severe cases. Vincristine binds to tubulin and disrupts axonal transport. In asymptomatic patients with defects in the peripheral myelin protein-22 gene, vincristine can unmask symptoms of Charçot-Marie-Tooth disease. It can also worsen mild cases of Charçot-Marie-Tooth disease and is contraindicated in these patients and in patients at risk for or showing clinical signs of undiagnosed hereditary neuropathy.

Cisplatin dose-limiting neurotoxicity generally occurs at cumulative doses of 250 to 500 mg/m², based on patient susceptibility. Patients typically have minor tingling in the distal limbs at the start of each cycle, which later resolves. Subacute numbness, paresthesia, and pain spread proximally as the cumulative dose increases; symptoms can become irreversible. Deep tendon reflexes are lost, and proprioception is disproportionately affected. Motor function is generally unaffected. Nerve conduction studies corroborate reduced sensory and normal motor responses. The drug binds to DNA in both prompts DNA repair and cell cycle entry in both dorsal root ganglia neurons and tumor cells. If the repair is unsuccessful, apoptosis may be triggered. The mechanism of toxicity is similar for carboplatin and oxaliplatin, but oxaliplatin can also cause an acute 1- to 2-day syndrome of cold-induced paresthesia, jaw and throat tightness, and cramps. Electrophysiological hallmarks of peripheral nerve hyperexcitability are seen and are thought to be caused by sodium channel dysfunction.⁶⁵

Paclitaxel, docetaxel, and newer emerging toxoids, used in breast, ovarian, and other cancers, cause dose-dependent sensory neuropathy. Toxicity is milder for the more potent docetaxel. In contrast to agents that disassemble microtubules (colchicine, vincristine, podophyllin), taxoids promote the assembly of large arrays of disordered microtubules. Interference with axonal transport is postulated.

Bortezomib (Velcade) is a member of a new class of anticancer drugs, proteasome inhibitors. This agent is primarily used to treat refractory myeloma. Peripheral neuropathy is a common and often treatment-limiting effect. Monitoring for neuropathy is necessary when using this agent.

Thalidomide is currently used in several neoplastic and rheumatological conditions and has antiangiogenic and anti-inflammatory properties. It causes a length-dependent sensory neuropathy, affecting both small- and large-diameter fibers. Many cases of sensory neuropathy were produced in the early 1960s but were overshadowed by the more infamous teratogenic effects. Neuropathy incidence ranges from 25% to 70%,⁶⁶ and recovery is often incomplete. The mechanism is unknown but the drug inhibits the activation of necrosis factor-κB, an important factor in sensory neuron survival. Onset appears to be related to cumulative dose.

Immunosuppressants

Tacrolimus (FK-506) is a calcineurin inhibitor and macrolide antibiotic extensively used in transplant medicine. It suppresses both humoral and cellular mediated immune responses. Although central toxicity is more common, numerous cases of peripheral neuropathy are reported: this manifests as a severe multifocal demyelinating neuropathy resembling chronic inflammatory demyelinating neuropathy; patients have been treated successfully with intravenous immunoglobulin or plasmapharesis.⁶⁷ Interestingly, this agent also has neuroregenerative activity, which differs from the calcineurin effects and is under investigation. Cyclosporin is rarely associated with neuropathy and sirolimus neuropathy has not been described.

Leflunomide, a novel disease-modifying rheumatoid arthritis treatment, has been associated with sometimes painful axonal sensorimotor polyneuropathy that had not been predicted in prerelease trials.⁶⁸ Onset is usually after 3 to 6 months of exposure and recovery is slow but less so if therapy is stopped within 30 days of initiation. The mechanism of neurotoxicity is unknown, although medication-induced vasculitis independent from rheumatoid arthritis vasculitis is suggested in some cases.^68,⁶⁹

Other Agents

With chronic high dosages (serum levels greater than 20μg/mL) of phenytoin, peripheral neuropathy is known to occur, based mostly on case series. Risk factors include prolonged use (longer than 10 years), supratherapeutic levels (greater than 20μg/mL), and low folate levels.⁷⁰ Neuropathy is rare at current dosages and usually produces only minimal symptoms.

Colchicine can produce a “neuromyopathy” with subacute vacuolar myopathy accompanied by mild distal pansensory axonal neuropathy. Chronic regular use and high serum levels are risk factors, which are presumed to alter axonal transport through microtubule disruption.⁷¹ Marked clinical improvement is expected after cessation.

Selected Toxins

Toxicity from heavy metals is a common patient concern but a rare cause of neuropathy.

Arsenic is the most common heavy metal to cause neuropathy: the course is slow in chronic exposure and more acute in cases of intentional poisoning. Arsenic trioxide is used to treat acute promyelocytic leukemia and can cause toxic neuropathy in a minority of treated patients. Sensory symptoms predominate initially, and pain and paresthesia precede leg weakness by days to weeks. Weakness can be severe. Stocking-glove sensory loss, especially of vibration and position sense, and distal loss of deep tendon reflexes are typical. Electrodiagnostic studies and neuropathology demonstrate signs of sensorimotor axonal loss. Chelation therapy is standard treatment.

Lead poisoning in adults may cause asymmetrical neuropathy, often more severe in the arms. Toxicity is usually accompanied by other poisoning symptoms, such as abdominal pain, but not by the encephalopathy typically seen in children. Blood levels over 30μg/dL are considered significant in adults. Motor symptoms predominate and can be multifocal, including the classic presentation of wrist and finger drop or foot drop. Chronic low-level exposure manifests as a distal, symmetrical sensory loss, mainly in the legs. Occupational lead poisoning was common in earlier eras, notably in silver miners, but is still occasionally encountered in battery workers, painters, pottery glazers, and other occupations; other exposure sources are known as well. Lead neuropathy is treated by exposure removal and chelation therapy.

Thallium exposure usually occurs through acute intentional poisoning and produces alopecia, gastrointestinal symptoms, and sensory neuropathy.

Mercury toxicity depends on the form of mercury—elemental or organic. The organic form (methyl and ethylmercury) is most toxic to the central nervous system, although distal paresthesia and sensory ataxia are prominent (presumably from dorsal root ganglion degeneration). Ventral roots and motor function are spared. Inorganic mercury salts were used in felt hat production, and toxicity produced memory loss and tremor (hence “mad as a hatter”). Inorganic mercury may be absorbed through the gastrointestinal tract, and volatile elemental mercury may be absorbed directly through the skin or lungs. Elemental mercury exposure is a rare cause of weakness and axonal motor and sensory fiber loss. Quicksilver is used in some ethnoreligious practices. Low-level exposure is a popular concern, but no evidence supports significant toxicity from dental amalgams; exposure from dietary fish consumption and thimeresol-containing vaccines is a more controversial issue.⁷²

Drugs of Abuse

Alcohol neuropathy is most commonly a slowly progressive predominantly sensory and sometimes painful neuropathy seen in chronic alcoholics. Symptoms and findings vary widely and are often overlooked by both patient and physician. Distal pain and dysesthesia, especially at night, are prominent; distal weakness and autonomic disturbances, although less common, are also seen. Examination reveals distal sensory loss and decreased deep tendon reflexes. Electrodiagnostic studies and nerve and muscle pathology show nonspecific, symmetrical sensory greater than motor axonal loss. Findings are common even in asymptomatic chronic alcoholics.⁷³ Whether the cause is a nutritional deficiency or a direct toxic alcohol effect remains controversial. Although vitamin levels are often reduced in alcoholics, measures correlate poorly with incidence of neuropathy. One recent study compared alcoholic patients with normal thiamin levels to alcoholic and nonalcoholic patients with thiamin deficiencies. Patients with normal thiamin levels had typical distal sensory neuropathy and nonalcoholic thiamin-deficient patients had subacute motor-predominant neuropathy. Alcoholic thiamin-deficient patients had a mixture of findings.⁷⁴ This study provided the best evidence to date of a direct toxic effect of ethanol on human peripheral nerve. Improvement after drinking cessation can occur, especially in mildly to moderately severe cases. Alcoholics are also more susceptible to nerve compression and entrapment, not limited to the classic “Saturday night palsy” affecting the radial nerve. The alcohol deterrent Dapsone can itself cause toxic neuropathy, especially at high doses, but this drug affects large-diameter sensory and motor fibers whereas alcohol disproportionately affects small fibers; however, confusion with alcoholic neuropathy sometimes occurs.⁷⁵ The toxin carbon disulfide (CS₂), a Dapsone metabolite, is another cause of toxic neuropathy and one possible mechanism of Dapsone toxicity.

Other drugs of abuse may lead to neuropathy, notably n-hexane and methyl-N-butyl ketone, found in widely available household solvents, fuels, and cleaning agents. Inhalation through the nose or mouth (huffing) of these materials is not rare in teens and young adults, especially if access to alcohol and hard drugs is limited. Axonal degeneration with sensory and motor impairment is seen, but focal conduction block associated with giant axonal swellings is also characteristic.^76,⁷⁷ Chronic industrial exposures generally lead to symmetrical axonal neuropathy. Selected other toxins are listed in Table 83-4.

TABLE 83-4 Selected Toxins Associated With Neuropathy

Heavy Metals

Miscellaneous

Hexacarbons (n-hexane)

Methyl n-butyl ketone

Methyl bromide

Organophosphates

Vacor

Seafood, Insect, and Animal-Borne Neurotoxins

Ciguatera

Paralytic shellfish poisoning

Puffer fish (fugu)

Tick paralysis

Tropical frog skin toxins

Polyneuropathy Associated With Dietary States

Thiamin deficiency may cause two different clinical syndromes: wet beriberi, in which congestive heart failure is the predominant sign, and dry beriberi, in which peripheral neuropathy predominates. Patients with thiamin deficiency have severe burning dysesthesia in the feet more than the hands, weakness and wasting of distal more than proximal muscles, trophic changes (shiny skin, hair loss), and distal sensory loss. Axonal neuropathy is the principal finding on nerve biopsy and electrodiagnostic studies. Treatment of beriberi should initially include parenteral B-complex vitamins followed by oral thiamin. Recovery is slow and may be incomplete. The distinctive features of alcoholic neuropathy were discussed earlier.

Niacin (nicotinic acid) deficiency causes pellagra, characterized by hyperkeratotic skin lesions. Peripheral neuropathy is frequent; symptoms usually improve with B-complex vitamins, which is preferable to simple niacin supplements.

Vitamin B₁₂ deficiency causes the classic clinical syndrome of subacute combined degeneration. Peripheral neuropathy is a component but the myelopathy is generally predominant. Painful paresthesia is present but sensory ataxia with loss of vibration and joint position sense predominates. Tendon reflexes are often diminished or absent. Malabsorption from a lack of intrinsic factor is the most common cause. Vitamin B₁₂ levels may be normal and the diagnosis can be established by elevated metabolites methylmalonic acid and homocysteine. Nitrous oxide also irreversibly inactivates cobalamin, producing the same syndrome. A single anesthetic dose in a patient with low or borderline vitamin B₁₂ levels or chronic exposure in individuals who abuse nitrous oxide, usually dental supplies or commercial whipped cream propellants, may result in secondary vitamin B₁₂ deficiency. Hematological abnormalities are usually absent in abuse cases.

Pyridoxine (B₆) deficiency produces a primarily sensory peripheral neuropathy, notably from the antituberculous drug, isoniazid, which increases pyridoxine excretion; hydralazine, phenelzine, and phenytoin also affect pyridoxine function. The neuropathy can be prevented by prophylactic pyridoxine administration. However, pyridoxine excess can itself lead to severe sensory neuropathy.

Vitamin E deficiency contributes to neuropathy in fat malabsorption syndromes including abetalipoproteinemia, congenital biliary atresia, pancreatic dysfunction, and surgical removal of large portions of the small intestine. The clinical syndrome resembles spinocerebellar degeneration, ataxia with severe proprioception and vibration loss, and hyporeflexia. Electrodiagnostic studies show sensory but not motor changes. There is limited but preliminary evidence that vitamin E can be neuroprotective in cisplatin ototoxicity and neuropathy.^78,⁷⁹

Strachan syndrome includes visual loss, oral ulcers, skin changes, and painful neuropathy. The syndrome was originally described in Jamaican sugar workers and a similar Cuban epidemic occurred in 1991; a syndrome with additional ataxia is seen in Nigeria. A nutrient-poor diet, especially one deficient in B vitamins, has been implicated.

Postgastrectomy Neuropathy

Bariatric surgery is rapidly increasing in popularity. Complications associated with the procedure are also increasingly noted. Peripheral neuropathy, most commonly sensorimotor axonal neuropathy, develops following surgery in a reported 5% to 16% of patients.^80,⁸¹ Neuropathy risk factors include rapid and marked weight loss, poor nutritional follow-up, surgical complications, and markers of poor nutrition, such as low serum albumin. Mononeuropathies and radiculoplexus neuropathy are less common. Nerve biopsy has shown axonal degeneration and perivascular inflammation. Malnutrition, especially cobalamin, folate, thiamin, and other vitamin deficiencies, is suspected, and aggressive supplementation and nutritional counseling are recommended. Immune and inflammatory factors are also proposed but not well established.

Celiac Neuropathy

Celiac disease is a chronic inflammatory enteropathy and is increasingly recognized, with an estimated prevalence of 0.3% to 1% in Western countries. Patients with HLA-DQ2 and HLA-DQ8 alleles may show sensitivity to wheat gluten, manifested by the presence of gliadin and transglutaminase autoantibodies. In addition to ataxia, peripheral neuropathy is a common neurological association and is not attributed to nutritional deficiencies.⁸² Some, however, are skeptical about this association.⁸³ The neuropathy is usually predominantly sensory and may be multifocal. Diagnosis is suspected with elevated antibody titers and confirmed by a duodenal biopsy demonstrating inflammation, crypt hyperplasia, and villous atrophy in small intestinal mucosa. Gastrointestinal—but generally not neurological—symptoms improve with a gluten-free diet. Nerve conduction studies are often normal but skin biopsy studies showed abnormalities in most patients in one small series.⁸⁴ Some, but not all, recommend testing for celiac disease in idiopathic neuropathy cases, especially if irritable bowel syndrome or other gastrointestinal symptoms are present.